Porphyrinic macrocycles bearing distinct patterns of substituents are important building blocks in diverse applications. Two distinct strategies have been applied to control the pattern of substituents about the porphyrin perimeter: (1) pre-arranging substituents in precursors to the porphyrinic macrocycle, or (2) preparing a porphyrin with a limited number of substituents and then introducing additional substituents by derivatization of the porphyrin. As an example of the former, the acid-catalyzed condensation of a dipyrromethane-dicarbinol+a dipyrromethane followed by oxidation provides a rational synthesis of ABCD-porphyrins [1]. The derivatization procedures in the latter approach include (i) halogenation of the porphyrin meso position and subsequent C—C bond formation (e.g., Suzuki, Heck, Sonogashira, or related palladium-mediated coupling reactions)[2] or (ii) nucleophilic attack of an alkyl or aryl lithium reagent followed by DDQ oxidation [3].
Porphyrins bearing only one or two meso-substituents (i.e., trans-AB-, trans-A2-, A-porphyrins) are of considerable interest owing to their compact size. A variety of trans-AB-porphyrins have been prepared although most also contain a full complement of β-substituents [4]. Porphyrins bearing only one or two meso substituents and lacking β-substituents in principle are available via the same methodology used to prepare ABCD-porphyrins, but traditionally the syntheses have been carried out by alternative routes. All known routes to trans-AB-, trans-A2-, and A-porphyrins are described below.
trans-AB-porphyrins: Synthetic approaches to β-unsubstituted trans-AB-porphyrins are illustrated based on the synthetic method (statistical or rational) and the substitution pattern of the precursors (Scheme 1, Routes 1-6). Statistical methods (Routes 1 [5] and 2 [6]) do not require functionalization of the dipyrromethane but result in a mixture of three porphyrins that requires chromatographic purification. The [2+2] MacDonald-type condensations of dipyrromethane derivatives include a dipyrromethane-1,9-dicarbinol+a dipyrromethane (Route 3, demonstrated for β-substituted substrates only) [7], a 5-substituted diformyldipyrromethane+a 5-substituted dipyrromethane (Route 4) [8], and a 5-substituted 1,9-bis(hydroxymethyl)dipyrromethane+a 5-substituted dipyrromethane (Route 5) [9]. In each case, the acid catalysis required to facilitate reaction at the α-substituent (e.g., formyl or hydroxymethyl group) often results in undesired rearrangement of the dipyrromethane reactants or oligopyrromethane intermediates, resulting in the formation of undesired porphyrinic macrocycles (i.e., scrambling) [9]. A related route (Route 6) developed in parallel with the work herein employs a 1,9-bis(N,N-dimethylaminomethyl)dipyrromethane+a dipyrromethane [10].

trans-A2-porphyrins: The synthesis of trans-A2-porphyrins can be achieved via the same routes as for trans-AB-porphyrins (where A=B in which case routes 1-5 are all rational) [9, 11, 12], as well as the self-condensation of a dipyrromethane-1-carbinol [12]. The simplest and most effective approach entails route 1, where dipyrromethane itself is reacted with aldehyde A [11].
A-porphyrins: Rational synthetic methods for preparing porphyrins bearing a single meso substituent have been applied exclusively with β-substituted dipyrromethanes (Scheme 2): (1) MacDonald [2+2] condensation of a diformyldipyrromethane+a dipyrromethane (Route 7) [13-15], and (2) a biladiene+aldehyde (Route 8) [15, 16]. A statistical synthesis afforded a β-unsubstituted A-porphyrin in 2-12% yield together with trans-A2-porphyrin byproducts (Route 9) [17]. An alternative approach to introduce a single meso substituent entails substitution of porphine [18, 19]. Porphyrins bearing a single meso substituent also have resulted as byproducts of scrambling processes with meso-unsubstituted dipyrromethanes [20,21] or tripyrrane [19].

In attempting to apply the methodology developed for the synthesis of ABCD-porphyrins to porphyrins bearing lesser substitution (e.g., trans-AB-, A-porphyrins), we were surprised to find that dipyrromethane reactants bearing a primary carbinol (route 5, Scheme 1) resulted in low yields of porphyrin (<5%) and the occurrence of scrambling [9]. By contrast, dipyrromethanes bearing a secondary carbinol (alkyl or aryl) typically afford yields of 10-35% and proceed without scrambling. Although such shortcomings can be circumvented in the synthesis of trans-AB-porphyrins through use of route 3, a number of substituents (mesityl [1], branched alkyl [22]) cannot be accommodated at the carbinol position. Moreover, no such solution is available for the synthesis of A-porphyrins.
We note also that the yields of trans-AB-porphyrins that bear β-substituents are often quite reasonable. The good yields are attributed to the following factors: (1) lack of a meso substituent at the dipyrromethane lessens propensity to scrambling, (2) the presence of β-substituents at the dipyrromethane enforces conformations inclined to cyclize, and (3) blockage of the β-position leaves the α-position as the only site available for reaction. These features are absent in β-unsubstituted trans-AB-porphyrins, and consequently, refined methods are required for preparing this seemingly simple class of compounds.